Members of the project team have identified a central role of the metabolic enzyme NNMT in the stroma of ovarian cancer. The target enzyme is highly expressed in the stroma of ovarian cancer metastases and is also expressed in primary cancer-associated fibroblasts (CAFs). Knockdown of the enzyme leads to a reversion of many of the features of CAFs and attenuates their ability to promote cancer cell growth both in vitro and in vivo. During this period, the project team successfully optimized a biochemical assay that was used to screen over 100,000 compounds for inhibitory activity against NNMT. Counter-screens against two components of the assay, and a related methyltransferase enzyme, were performed to filter out the false positives. Several chemotypes were identified with ideal activity profiles, and in vitro target engagement and cellular inhibition were assessed. Medicinal chemistry optimization of select hits is currently underway to further improve potency and physiochemical properties.